H.influenzae, a strict human pathogen, causes widespread and serious disease in both pediatric human populations (infants and children) and in adults and elderly. Pediatric diseases include mucosal surface diseases such as middle ear infections as well as invasive diseases such as meningitis, epiglottitis, septic arthritis and cellulitis. These diseases are leading causes of deafness and mental retardation and some of them can be fatal. While H.influenzae causes only about 30% of all otitis media, it is the most frequent cause of recurrent otitis media. Loss of hearing (and its accompanying retardation in learning) increases with the number of otitis episodes. Adult diseases are principally mucosal and include chronic bronchitis, sinusitis and pneumonia. H.influenzae is increasingly recognized as an important pathogen in adult and elderly populations.
Mucosal H.influenzae diseases are mainly caused by non-type b encapsulated and non-encapsulated (NT.sub.b H.influenzae) strains of the organism and invasive H.influenzae diseases are almost exclusively caused by type b encapsulated strains (H.influenzae b). No vaccine exists for NT.sub.b H.influenzae disease. A Type b capsular polysaccharide vaccine is available. The vaccine consisting of purified polyribitol phosphate (PRP), is partially effective but has several serious disadvantages. It is not antigenic or effective in the most susceptible group, that is children under the age of 18 months, and it is not completely effective in older children or in all populations. A new version of this vaccine has been recently licensed in which the polysaccharide is combined with a protein to enhance the polysaccharide's antigenicity. The conjugate vaccine appears more effective in younger populations. Neither of these vaccines gives any protection against mucosal H. influenzae diseases and neither of them prevents transmission of H.influenzae infection or colonization of the human nasopharynx.
We have discovered four morpholological and adhesion classes of pili on H.influenzae clinical isolates from different diseases, anatomical sites, ethnic groups and geographical areas. The principal pilus class, termed LKP pili, has been characterized in detail and evaluated as a purified pilus vaccine in a valid animal model of H.influenzae disease. LKP pili adhere to human erythrocytes, as do many of the pili used in other vaccines. Both NT.sub.b H.influenzae and H.influenzae b strains can express LKP pili of the same serotypes, opening the possibility that one purified LKP pilus vaccine consisting of mixed serotypes can protect against several H.influenzae diseases. Although at least eight different serotypes of LKP pili have been found, only a restricted number of them occur frequently on clinical isolates.
Purified LKP pilus vaccines have been tested in the chinchilla model of otitis media. A single pilus vaccine was safe, antigenic, and protected against both nasopharyngeal colonization and middle ear disease. Excellent protection was obtained irrespective of whether inoculation of the bacteria was directly into the middle ear or into the nasopharynx, and whether inoculation was with the piliated phase of the nonpiliated phase of H.influenzae bacteria. When inoculation was with the nonpiliated phase, a rapid shift to the piliated phase occurred in the nasopharynges and middle ears of the animals. This observation is consistent with an important role for LKP pili in colonization and virulence. Pilus vaccine immunization completely eliminated piliated phase bacteria from both anatomical sites. Protection was shown to be LKP pilus type specific.